Dual expression of immunoreactive estrogen receptor β and p53 is a potential predictor of regional lymph node metastasis and postoperative recurrence in endometrial endometrioid carcinoma

Obata, Tohru; Nakamura, Mitsuhiro; Mizumoto, Yasunari; Iizuka, Takashi; Ono, Masanori; Terakawa, Jumpei; Daikoku, Takiko; Fujiwara, Hiroshi

doi:10.1371/journal.pone.0188641

Cited by 19 publications

(23 citation statements)

References 38 publications

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“…The p53-positive rate is 17–45% in all histological types of endometrial carcinomas. In type-I endometrial cancer, the p53-positive rate was 10–44%, whereas a high rate of p53 expression was observed in 30–86% of type-II endometrial cancer [59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75] (Table 1). Overexpression of p53 is a poor prognostic factor in both type-I and type-II endometrial cancer.…”

Section: Significance Of P53 In Gynecologic Cancersmentioning

confidence: 99%

The Association and Significance of p53 in Gynecologic Cancers: The Potential of Targeted Therapy

Nakamura

Obata

Daikoku

et al. 2019

IJMS

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Dysfunction of p53 is observed in the many malignant tumors. In cervical cancer, p53 is inactivated by degradation through the complex with human papilloma virus (HPV) oncoprotein E6 and E6-associated protein (E6AP), an E3 ubiquitin protein ligase. In endometrial cancer, overexpression of p53 in immunohistochemistry is a significant prognostic factor. A discrepancy between p53 overexpression and TP53 mutations is observed in endometrioid endometrial cancer, indicating that the accumulation of p53 protein can be explained by not only gene mutations but also dysregulation of the factors such as ERβ and MDM2. Furthermore, the double-positive expression of immunoreactive estrogen receptor (ER) β and p53 proteins is closely associated with the incidence of metastasis and/or recurrence. High-grade serous ovarian carcinoma (HGSC) arises from secretary cells in the fallopian tube. The secretary cell outgrowth (SCOUT) with TP53 mutations progresses to HGSC via the p53 signature, serous intraepithelial lesion (STIL), and serous intraepithelial carcinoma (STIC), indicating that TP53 mutation is associated with carcinogenesis of HGSC. Clinical application targeting p53 has been approved for some malignant tumors. Gene therapy by the adenovirus-mediated p53 gene transfer system is performed for head and neck cancer. A clinical phase III trial using MDM2/X inhibitors, idasanutlin (RG7388) combined with cytarabine, is being performed involving relapse/refractory acute myeloid leukemia patients. The use of adenoviruses as live vectors which encode wild-type p53 has given promising results in cervical cancer patients.

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Section: Significance Of P53 In Gynecologic Cancersmentioning

confidence: 99%

The Association and Significance of p53 in Gynecologic Cancers: The Potential of Targeted Therapy

Nakamura

Obata

Daikoku

et al. 2019

IJMS

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“…In a previous study, we were able to show, that expression of ERβ was even sufficient to significantly inhibit proliferation of hormone-independent COS-1 cells and to increase apoptosis even in the absence of E2 [30]. However, the role of this receptor in endometrial cancer is still controversial, as some studies reported downregulation of ERβ in endometrial cancer [7–9], and others observed increased expression of this receptor in endometrial tumor tissue or its association with disease progression [10–12]. Concordant studies on other cancer entities demonstrated that ERβ expression is decreased or lost in a variety of tumors when compared to normal tissue, a fact that was reported to have negative consequences on survival or therapy of different cancer entities [31–35].…”

Section: Discussionmentioning

confidence: 99%

“…With regard to endometrial cancer, the role of this receptor is still controversial. Whereas various studies report downregulation of ERβ in endometrial cancer [7–9], others observed increased expression of this receptor in endometrial tumor tissue or its association with disease progression [10–12]. From other hormone dependent tissues like the breast, ERβ is known to exert inhibitory effects on proliferation and invasion, both dependent and independent from presence of ERα [13–15].…”

Section: Introductionmentioning

confidence: 99%

Knockdown of estrogen receptor β increases proliferation and affects the transcriptome of endometrial adenocarcinoma cells

et al. 2019

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Background Estrogen receptor β (ERβ) has been repeatedly suggested to play important roles in hormone-dependent cancer like in tumors of the breast, ovary or prostate. In this study, we intended to further elucidate its role in endometrial cancer. Methods For this purpose, we knocked down ERβ expression in two endometrial cancer cell lines, the ERα-negative/ERβ-positive line HEC-1A and the ERα/β-positive cell line RL95/2, by means of siRNA transfection. Cell proliferation after transfection was assessed using the fluorescent CTB Assay (Promega). In order to elucidate possible molecular mechanisms which might underlie the effect on proliferation, we performed transcriptome analyses by means of human Affymetrix Human Gene Chip 2.0. Additionally, we treated the employed cell lines with different ERβ modulators to examine their effect on proliferation. Results siRNA-mediated knockdown of ERβ significantly increased proliferation of both endometrial cancer cell lines. In HEC-1A cells, proliferation was significantly increased 4, 5 and 6 days after transfection, with a maximum of about 1.7-fold ( p < 0.05) on day 6. Endometrial RL95/2 cells with an ERβ knockdown exhibited a clearly enhanced proliferation on day 3 and days 4 to 8, when even 2.4-fold higher numbers of viable cells were detected ( p < 0.01). Transcriptome analysis revealed that this was accompanied by increased expression of several genes being known to be upregulated in cancer, including proliferation-associated genes and oncogenes, and by repression of genes associated with differentiation, apoptosis or growth inhibition. Corroborating the observed knockdown effects, treatment with the ERβ antagonists PHTTP and (R, R) THC was also able to induce proliferation of both cell lines. Conclusions Our data clearly support the putative role of ERβ as tumor suppressor in endometrium as previously suggested in studies on other tissues and encourage further studies to find out to what extent this molecule might be a potential therapy target in this cancer entity. Electronic supplementary material The online version of this article (10.1186/s12885-019-5928-2) contains supplementary material, which is available to authorized users.

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“…Nonetheless, some studies have demonstrated ERβ positivity to be correlated with a more aggressive clinical outcome15 and with the proliferation marker, Ki-67 43–45. ERβ has also been identified as a novel activator of wild-type p53-dependent transcription, which leads to poorer survival of luminal breast cancer cells 42 46–50…”

Section: Discussionmentioning

confidence: 99%

Characteristics, behaviour and role of biomarkers in metastatic triple-negative breast cancer

Goto¹,

Thike

Ong

et al. 2019

J Clin Pathol

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AimsCharacterising the factors responsible for metastatic triple-negative breast cancer (TNBC) is of significant importance, considering its high mortality rate and scant data. In this study, we evaluated the characteristics, clinical behaviour and role of biomarkers (androgen receptor (AR), oestrogen receptor beta (ERβ) and p53) in metastatic TNBC.MethodsImmunohistochemistry was performed for AR, ERβ and p53 on 125 primary TNBCs with known metastasis and correlated with clinicopathological parameters and outcome. AR and p53 mRNA profiling was also carried out on 34 tumours from the same series and correlated with outcomes.ResultsIn this cohort, grade 3 and pT2 tumours predominated. The most common site for metastasis was the lung and pleura (41, 32.8%), and 15 (12.0%) cases demonstrated metastasis in multiple sites. Among these, 92% of tumours metastasised without preceding local recurrences. Five- and ten-year overall survival (OS) rates were 27% and 7.2%, while 5- and 10- year survival rates after metastasis were 9.6% and 3.2% respectively. AR, ERβ and p53 protein expressions were observed in 16%, 96.8% and 58.1% of tumours, respectively. A combinational phenotype of AR-ERβ+p53+ tumours was associated with poorer OS (HR 1.543, 95%CI 1.030 to 2.310, p=0.035). Higher AR mRNA levels were significantly associated with favourable OS (p=0.015) and survival after metastasis (p=0.027).ConclusionsMetastatic TNBC harboured aggressive behaviour and displayed predominantly visceral metastasis with most metastatic events occurring without intervening local recurrences. A combinational phenotype of AR-ERβ+p53+ was significantly associated with poorer OS.

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Dual expression of immunoreactive estrogen receptor β and p53 is a potential predictor of regional lymph node metastasis and postoperative recurrence in endometrial endometrioid carcinoma

Cited by 19 publications

References 38 publications

The Association and Significance of p53 in Gynecologic Cancers: The Potential of Targeted Therapy

The Association and Significance of p53 in Gynecologic Cancers: The Potential of Targeted Therapy

Knockdown of estrogen receptor β increases proliferation and affects the transcriptome of endometrial adenocarcinoma cells

Characteristics, behaviour and role of biomarkers in metastatic triple-negative breast cancer

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